Process for the preparation of chemical compounds

ABSTRACT

The invention provides a process for preparing a compound of formula (I)                    
     and pharmaceutically acceptable derivatives thereof wherein: 
     R 0  and R 1  are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkoxy substituted by one or more fluorine atoms; 
     R 2  is H, C 1-6 alkyl, C 1-6 alkyl substituted by one or more fluorine atoms, C 1-6 alkoxy, C 1-6 hydroxyalkyl, SC 1-6 alkyl, C(O)H, C(O)C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkoxy substituted by one or more fluorine atoms, halogen, CN, CONR 4 R 5 , CO 2 H, CO 2 C 1-6 alkyl, or NHSO 2 R 4 ; 
     R 3  is H or phenyl substituted by SO 2 C 1-6 alkyl or SO 2 NH 2 ; 
     R 4  and R 5  are independently selected from H, C 1-6 alkyl, phenyl, phenyl substituted by one or more atoms or groups R 6 , or together with the nitrogen atom to which they are attached form a saturated 4 to 8 membered ring 
     R 6  is halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 alkoxy substituted by one or more fluorine atoms; 
     which comprises rearrangement of an azirine of formula (II)                    
      wherein R 0  to R 3  are as defined for formula (I), or a protected derivative thereof, in the presence of a catalyst and a solvent.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a Rule 371 Application of PCT Application No.US01/13801, filed Apr. 27, 2001, which claims priority to U.S.application Ser. No. 60/200,400, filed Apr. 28, 2001.

BACKGROUND OF THE INVENTION

This invention relates to a process for the preparation ofpyrazolopyridine derivatives.

Pyrazolopyridine derivatives of formula (Ia)

and pharmaceutically acceptable derivatives thereof in which:

R^(0a) and R^(1a) are independently selected from H, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, or C₁₋₆alkoxy substituted by one or more fluorine atoms;

R^(2a) is H, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorineatoms, C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms; and

R^(3a) is C₁₋₆alkyl or NH₂;

are disclosed in WO 00/26216 (Glaxo Group Limited), unpublished at thepriority date of the instant application.

Pyrazolopyridine derivatives of formula (Ib)

and pharmaceutically acceptable derivatives thereof in which:

R^(0b) and R^(1b) are independently selected from H, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, or C₁₋₆alkoxy substituted by one or more fluorine atoms;

R^(2b) is halogen, CN, CONR^(4b)R^(5b), CO₂H, CO₂C₁₋₆alkyl, orNHSO₂R^(4b);

R^(3b) is C₁₋₆alkyl or NH₂; and

R^(4b)and R^(5b) are independently selected from H, C₁₋₆alkyl, phenyl,phenyl substituted by one or more atoms or groups (selected fromhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, or C₁₋₆alkoxy substituted by one or morefluorine atoms), or together with the nitrogen atom to which they areattached form a saturated 4 to 8 membered ring;

are disclosed in WO 00/52008 (Glaxo Group Limited), also unpublished atthe priority date of the instant application.

As described in WO 00/26216 and WO 00/52008, the compounds of formulae(Ia) and (Ib) are potent and selective inhibitors of COX-2 and, as such,are of use in human and veterinary medicine, particularly in thetreatment of the pain (both chronic and acute), fever and inflammationof a variety of conditions and diseases. Such conditions and diseasesare well known in the art and include arthritis, such as rheumatoidarthritis; and degenerative joint diseases, such as osteoarthritis.

Several processes for the preparation of the compounds of formulae (Ia)and (Ib) are respectively disclosed in WO 00/26216 and WO 00/52008,inter alia the thermal rearrangement of an azirine in1,2,4-trichlorobenzene at reflux.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a particularly advantageous process, nothitherto disclosed, of preparing compounds of formulae (Ia) and (Ib)and, more particularly, intermediates for use in the preparation of suchcompounds, which comprises catalytic rearrangement of an azirine to givethe corresponding pyrazolopyridine.

Accordingly, in a first aspect, the instant invention provides a processfor the preparation of a pyrazolopyridine derivative of formula (I)

and pharmaceutically acceptable derivatives thereof in which:

R⁰ and R¹ are independently selected from H, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, or C₁₋₆alkoxy substituted by one or more fluorine atoms;

R² is H, C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorine atoms,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulfonyl, C₁₋₆alkoxy substituted by one or more fluorine atoms,halogen, CN, CONR⁴R⁵, CO₂H, CO₂C₁₋₆alkyl, or NHSO₂R⁴;

R³ is H or phenyl substituted by SO₂C₁₋₆alkyl or SO₂NH₂;

R⁴ and R⁵ are independently selected from H, C₁₋₆alkyl, phenyl, phenylsubstituted by one or more atoms or groups R⁶, or together with thenitrogen atom to which they are attached form a saturated 4 to 8membered ring; and

R⁶ is halogen, C₁₋₆alkyl, C₁₋₆alkoxy or C₁₋₆alkoxy substituted by one ormore fluorine atoms;

which comprises rearrangement of an azirine of formula (II),

 wherein R⁰ to R³ are as defined for formula (I), or a protectedderivative thereof, in the presence of a transition metal catalyst and asolvent.

In a further aspect, the transition metal catalyst is selected from acopper (II), iron (II), iron (III) or molybdenum catalyst; preferablycopper (II) sulfate, molybdenum hexacarbonyl, iron (II) chloride, oriron (III) chloride; more preferably iron (II) chloride or iron (III)chloride.

In a further aspect, the solvent is an organic solvent with a boilingpoint of 40° C. or greater. Conveniently, the solvent is an ether suchas dimethoxyethane, dioxane or tetrahydrofuran, preferablydimethoxyethane, an ester such as ethyl acetate or butyl acetate, aprotic solvent such as methanol, a dipolar aprotic solvent such asdimethylformamide or acetonitrile, a hydrocarbon solvent such as hexaneor toluene, preferably toluene, or a chlorinated solvent such asdichloromethane.

In a further aspect, the rearrangement is effected between ambienttemperature and reflux. Conveniently, the temperature is from 40° C. toabout 120° C., such as about 50 to about 100° C., preferably 60-90° C.

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ and R¹ areindependently selected from H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, orC₁₋₆alkoxy substituted by one or more fluorine atoms; R² is H,C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorine atoms,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or more fluorineatoms; and R³ is H or phenyl substituted by SO₂C₁₋₆alkyl or SO₂NH₂.

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ and R¹ areindependently H, halogen, C₁₋₆alkyl, or C₁₋₆alkoxy; R² is C₁₋₃alkylsubstituted by one or more fluorine atoms; and R³ is H or phenylsubstituted by SO₂C₁₋₃alkyl or SO₂NH₂.

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ and R¹ areindependently H, F, Cl, C₁₋₃alkyl (e.g. methyl), or C₁₋₃alkoxy (e.g.ethoxy); R² is C₁₋₃alkyl substituted by one or more fluorine atoms (e.g.trifluoromethyl); and R³ is H or phenyl substituted by SO₂CH₃ or SO₂NH₂.

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ is F, Cl, orC₁₋₃alkyl (e.g. methyl) or C₁₋₃alkoxy (e.g. ethoxy); R¹ is H; R² isC₁₋₃alkyl substituted by one or more fluorine atoms (e.g.trifluoromethyl); and R³ is H or phenyl substituted by SO₂CH₃ or SO₂NH₂.

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ is at the 3-or 4-position of the phenyl ring, and R² is at the 6-position of thepyrazolopyridine ring, as defined in formula (I).

In a further aspect the invention provides a process for the preparationof a pyrazolopyridine derivative of formula (I) wherein: R⁰ is F, R¹ isH, R² is CF₃ and R³ is phenyl substituted by SO₂NH₂.

In a preferred aspect the invention provides a process for thepreparation of a pyrazolopyridine derivative of formula (I) wherein: R³is H.

In a further aspect the invention provides novel compounds of formula(I) wherein R³ is H.

The process according to the invention is surprisingly advantageous,being easy to carry out and proceeding efficiently and in good yield.

By pharmaceutically acceptable derivative is meant any pharmaceuticallyacceptable salt, solvate or ester, or salt or solvate of such ester, ofthe compounds of formula (I), or any other compound which uponadministration to the recipient is capable of providing (directly orindirectly) a compound of formula (I) or an active metabolite or residuethereof.

It will be appreciated by those skilled in the art that the compounds offormula (I) may be modified to provide pharmaceutically acceptablederivatives thereof at any of the functional groups in the compounds. Ofparticular interest as such derivatives are compounds modified at thebenzenesulphonamide function to provide metabolically labilebenzenesulphonamides.

It will be appreciated that, for pharmaceutical use, the salts referredto above will be the physiologically acceptable salts, but other saltsmay find use, for example in the preparation of compounds of formula (I)and the physiologically acceptable salts thereof.

Suitable pharmaceutically acceptable salts of the compounds of formula(I) include acid addition salts formed with inorganic or organic acids,preferably inorganic acids, e.g. hydrochlorides, hydrobromides andsulphates.

The term ‘halogen’ is used to represent fluorine, chlorine, bromine oriodine.

The term ‘alkyl’ as a group or part of a group means a straight orbranched chain alkyl group, for example a methyl, ethyl, n-propyl,i-propyl, n-butyl, s-butyl or t-butyl group.

The term ‘one or more fluorine atoms’ means up to and including fivefluorine atoms; preferably up to and including three fluorine atoms e.g.trifluoromethyl.

As will be appreciated by those skilled in the art, the preparation ofcompounds of formula (I) in which R³ is phenyl substituted bySO₂C₁₋₆alkyl or SO₂NH₂ may be achieved from compounds of formula (I)wherein R³ is H via halogenation followed by coupling with a suitableboronic acid, as disclosed in WO 00/26216 and WO 00/52008.

As will be appreciated by those skilled in the art, the preparation ofpharmaceutically acceptable derivatives of formula (I) may convenientlybe effected by a process which comprises rearrangement of acorresponding derivative of formula (II) according to the conditionsdescribed above.

Compounds of formula (II), including derivatives corresponding topharmaceutically acceptable derivatives of formula (I), may be preparedby any method known in the art for the preparation of compounds ofanalogous structure.

Compounds of formula (II) may be prepared from an oxime of formula (III)

by conventional means. Conveniently the oxime is dissolved in a solventsuch as an ether (e.g. dimethoxyethane), cooled to about 0° C. and thentreated with either an anhydride (e.g. trifluoroacetic anhydride) ormethanesulfonyl chloride. The reaction mixture is then treated with abase, such as an amine (e.g. triethylamine), and the mixture thenallowed to warm to ambient temperature.

Compounds of formula (III) may be prepared from a ketone of formula (IV)

by conventional means. Conveniently the reaction is effected withhydroxylamine or a salt thereof (e.g. hydroxylamine hydrochloride), in asolvent such as an alcohol (e.g. methanol) at elevated temperature.

Compounds of formula (IV) may be prepared by reacting a compound offormula (V)

with a compound of formula (VI)

under conventional conditions. Conveniently the compound of formula (VI)is a chloro derivative and the reaction is effected in the presence of astrong base, such as an inorganic hydride (e.g. sodium hydride) and atabout 40 to 50° C.

Compounds of formulae (V) and (VI) are known compounds or may beprepared in a conventional manner.

As will be appreciated by those skilled in the art it may be necessaryor desirable at any stage in the synthesis of compounds of formula (I)to protect one or more sensitive groups in the molecule so as to preventundesirable side reactions.

The protecting groups used in the preparation of compounds of formula(I) may be used in a conventional manner. See, for example, thosedescribed in ‘Protective Groups in Organic Synthesis’ by Theodora W.Green and Peter G M Wuts, second edition, (John Wiley and Sons, 1991),incorporated herein by reference, which also describes methods for theremoval of such groups.

Conveniently, compounds of formula (I) are isolated following work-up inthe form of the free base. Pharmaceutically acceptable acid additionsalts of the compounds of formula (I) may be prepared using conventionalmeans.

Solvates (e.g. hydrates) of a compound of formula (I) may be formedduring the work-up procedure of one of the aforementioned process steps.

When a particular isomeric form of a compound is desired the requiredisomer may conveniently be separated using preparative high performanceliquid chromatography (h.p.l.c.).

The following Examples illustrate, but do not in any way limit, theinvention. All temperatures are in ° C. Flash column chromatography wascarried out using either Malinckrodt Silica Gel 60, 23-400 mesh or MerckSilica Gel 60 (230-400 mesh). Thin layer chromatography (Tlc) wascarried out on silica plates. NMR was carried out on either a VarianINOVA 300 MHz or 400 MHz spectrometer or a Bruker 400 MHz spectrometer,unless otherwise stated. Chemical shifts are given, with respect totetramethylsilane as internal chemical shift reference, in δ ppm. Thefollowing abbreviations are used: Me, methyl; Et, ethyl; Ph, phenyl; Ac,acetyl; DME, 1,2-dimethoxyethane; TFAA, trifluoroacetic anhydride; MsCl,methanesulfonyl chloride; IPA, 2-propanol; TFA, trifluoroacetic acid; s,singlet; d, doublet; t, triplet; q, quartet and m, multiplet. Unlessotherwise noted, gradient HPLC analysis was performed using a 50 mm×2 mmLuna C-18(2) 3 micron reverse phase column, flow rate=1 ml/min, uvdetection at 220 nm. Mobile phase A=0.05% TFA in water, mobile phaseB=0.05% TFA in acetonitirile. Gradient: 0-95% B over 8 minutes.Retention times (RT) are given in minutes. AUC is defined as area underthe curve. Biotage chromatography was performed on a silica gelcartridge (180 mm×450 mm) at 60 psi. LC/MS analysis was performed usingan HP1050 LC/autoinjector and a 3.3 cm×4.6 mm ID, 3 um ABZ+PLUS columnwith a flow rate of 3 ml/min, except where stated otherwise. The mobilephase was varied with time according to the following table whereinsolvent A is 0.1% aqueous formic acid+10 mMolar ammonium acetate andsolvent B is 95% acetonitrile+0.05% aqueous formic acid.

Time (min) % A % B 0.00 100 0 0.70 100 0 4.20 0 100 5.30 0 100 5.50 1000

Mass spectra were recorded using a Micromass Series II massspectrometer.

EXAMPLE 1 2-(3-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i)1-(3-Fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone

A reaction vessel was charged with 2-chloro-5-trifluoromethylpyridine (8g, 44 mmol), 3-fluoroacetophenone (6.4 g, 46 mmol) and DME (56 ml).Sodium hydride (as a 60% oil dispersion, 5.8 g, 145 mmol) was added inportions to the mixture under nitrogen at room temperature. The mixturewas stirred at 40-45° C. overnight. Upon the completion of the reaction,aqueous NH₄Cl solution (240 ml) was added to the reaction mixture atroom temperature. The mixture was stirred for 0.5 hr and filtered. Thecake was washed with water, slurried in hexanes (32 ml) and dried in avacuum oven to give 10.44 g (84%) of the title compound (a mixture ofketone and enol isomers) as a solid with purity 99% AUC by HPLC(Phenomenex Luna 3μ cyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UVdetection: 220 nm. Eluent: 75% A, 25% B. A: 80/20/0.05water/acetonitrile/TFA. B: 20/80/0.05 water/acetonitrile/TFA ).

¹H-NMR (DMSO-d₆) (enol form): δ 6.60 (1H, s), 7.28 (1H, t, J=8.4), 7.42(1H, d, J=8.4), 7.5 (1H, q, J=7, J=7.6), 7.62 (1H, d, J=10.0), 7.70 (1H,d, J=7.6), 8.10 (1H, d, J=8.2), 8.78 (1H, s).¹H-NMR (CDCl₃) (a mixtureof ketone and enol isomers): δ 4.59 (s), 6.17 (s), 7.12-7.96 (m), 8.65(s), 8.87 (s).

ii) 1-(3-Fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

A reaction vessel was charged with1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (2 g, 7mmol), hydroxylamine (2.2 g, 32 mmol), 10% NaOH aqueous solution (11 ml,27 mmol) and methanol (24 ml). The reaction mixture was heated to 70° C.and stirred at 70° C. for 3 hrs. It was then cooled to room temperatureand water (12 ml) was added. The mixture was stirred at 0° C. for 1 hr.The solids were collected on a filter, washed with water, and driedunder vacuum at 50° C. overnight to provide 1.9 g (91%) of the titlecompound as a solid with purity 99% AUC by HPLC (Phenomenex Luna 3μcyano, 100 mm×4.6 mm. Flow rate: 1 ml/min. UV detection: 220 nm. Eluent:75% A, 25% B. A: 80/20/0.05 water/acetonitrile/TFA. B: 20/80/0.05water/acetonitrile/TFA).

¹H-NMR (DMSO-d₆): δ 4.38 (2H, s), 7.18 (1H, t, J=8.7), 7.41 (1H, q,J=8.1, J=7.2), 7.53 (2H, t, J=9.3), 8.11 (1H, d, J=8.1), 8.83 (1H, s).

iii) 2-[3-(3-Fluorophenyl)-2H-azirin-2-yl]-5-trifluoromethylpyridine

To a solution of1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (3.3g, 11.06 mmol) in CH₂Cl₂ (50 ml) was added Et₃N (6.2 ml, 44.24 mmol).The solution was cooled to 0° C. and TFAA (1.9 ml, 13.27 mmol) was addeddropwise over 30 min. After the addition was complete, the solution wasstirred for an additional 5-10 min at 0° C. and then warmed to roomtemperature. After stirring for 1 hour at ambient temperature, thereaction was judged complete by HPLC and cooled to 0° C. Water (50 ml)was added and the layers were separated. The aqueous layer was extractedwith CH₂Cl₂ (2×5 ml), and the combined organic extracts were dried overMgSO₄. After filtration and concentration under reduced pressure, theresidue was purified using column chromatography on silica gel (elutionwith 5-10% EtOAc in hexanes) to afford 2.5 g (81%) of the title compoundas a yellow waxy solid.

¹H NMR (CDCl₃, 400 MHz) δ 8.75 (1H, s), 7.82 (1H, d, J=8.2), 7.69 (1H,d, J=7.7), 7.59 (1H, d, J=8.4), 7.54 (1H, m), 7.32 (1H, m), 7.21 (1H, d,J=8.2), 3.54 (1H, s). HPLC; RT=5.4 min. AUC=97%.

iv) 2-(3-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a solution of2-[3-(3-fluorophenyl)-2H-azirin-2-yl]-5-trifluoromethylpyridine (2.2 g,7.85 mmol) in DME (10 ml) was added FeCl₂ (10 mg, 0.079 mmol). Thesolution was warmed to 75° C. and stirred for 2 hours. The reaction wascooled to room temperature and added to H₂O (180 ml). The resultantsuspension was cooled to 0° C. and stirred for 30 min. The solid wasisolated by filtration and partially dried via airflow.Recrystallization of the crude product in IPA afforded 1.34 g (60%) ofthe title compound as an off-white solid.

¹H NMR (CDCl₃, 400 MHz): δ 8.79 (1H, s), 7.72 (1H, d, J=8.6), 7.66 (1H,d, J=8), 7.61 (1H, d, J=9.3), 7.42 (1H, m), 7.23 (1H, d, J=8), 7.09 (1H,m), 6.87 (1H, s). HPLC; RT=6.3 min, AUC=99%.

EXAMPLE 2 2-(3-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(3-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (10.0g, 33.53 mmol) in DME (38 ml) was added MsCl (2.6 ml, 33.53 mmol) at 0°C. The suspension was stirred for 15-20 min and then Et₃N (9.3 ml, 67.1mmol) dissolved in DME (4 ml) was added dropwise at a rate to maintainthe temperature ≦5° C. After the addition was complete, the suspensionwas warmed to room temperature and stirred for 1 hour. Additional Et₃N(0.47 ml, 3.35 mmol) was added and the solution was stirred for 15 minat 30-35° C. The suspension was cooled to room temperature and filteredto remove the salts. The cake was washed with twice with DME (10 ml) andthe filtrate was transferred to a clean reaction flask. To the filtratewas added FeCl₂ (42 mg, 0.34 mmol) at room temperature. The solution washeated to 70° C. and stirred for 30 min. After cooling the solution to40° C., H₂O was added (80 ml). The resultant suspension was cooled to0-5° C. and stirred for 30 min. The solid was isolated by filtration andpartially dried via airflow. The solid was further dried under reducedpressure (20 in Hg Vacuum) at 50° C. to afford 7.91 g (84%) of the titlecompound as a beige solid.

¹H NMR (CDCl₃, 400 MHz) 8.79 (1H, s), 7.72 (1H, d, J=8.6), 7.66 (1H, d,J=8), 7.61 (1H, d, J=9.3), 7.42 (1H, m), 7.23 (1H, d, J=8), 7.09 (1H,m), 6.87 (1H, s); HPLC; RT=6.3 min, AUC=99%.

EXAMPLE 3 2-(3-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(3-fluorophenyl)-2-[5-(trifluoromethyl)-2-pyridinyl]ethanone oxime(5.0 g, 16.77 mmol) in DME (20 ml) at −5° C. was added MsCl (1.3 ml,16.77 mmol). The suspension was stirred at −5° C. for 10-15 min, andthen Et₃N (4.8 ml, 34.37 mmol) was added at a rate to maintain thetemperature at or below 0° C. After the addition was complete, thesuspension was warmed to room temperature. After 1 h an additional 0.5eq. of Et₃N was added to drive the reaction to completion. After anadditional 0.5 h stirring, the suspension was filtered into a cleanflask. DME (10 ml) was used to wash the salt cake. To the solution wasadded FeCl₃ (27 mg, 0.167 mmol) in one portion. The resultant darksolution was heated to 70° C. and stirred for 1.5 h. The solution wasthen cooled to room temperature before the addition of H₂O (50 ml) andethyl acetate (100 ml). The layers were separated and the ethyl acetatelayer was washed with 1 M HCl (50 ml) followed by brine (50 ml). Thesolution was filtered through a short plug of silica to remove anyresidual iron salts. The solution was concentrated under reducedpressure to afford 4.32 g (92%) of the title compound as a tan solid.

¹H NMR (CDCl₃, 400 MHz) 8.79 (1H, s), 7.72 (1H, d, J=8.6), 7.66 (1H, d,J=8), 7.61 (1H, d, J=9.3), 7.42 (1H, m), 7.23 (1H, d, J=8), 7.09 (1H,m), 6.87 (1H, s); HPLC; RT=6.3 min, AUC=98.3%.

EXAMPLE 42-(3-Chloro-4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(3-Chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanoneOxime

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 7.2 g, 180 mmol), DME (60 ml) and2-chloro-5-trifluoromethylpyridine (10 g, 55.1 mmol).3-Chloro-4-fluoroacetophenone (9.8 g, 56.9 mmol) in DME (20 ml) wasadded in portions to the mixture under nitrogen at room temperature. Themixture was stirred at ambient temperature for one hour then at 40-45°C. overnight. Upon the completion of the reaction, the mixture wascooled to 5° C. and 10% aqueous sodium hydroxide solution (30 ml) wasslowly added to the reaction mixture followed by methanol (60 ml) thenhydroxylamine hydrochloride (19.1 g, 357 mmol). The mixture was heatedto 72° C. for 4 hours then cooled and diluted with water (1500 ml) withstirring. The resulting solid was removed by filtration and dried undervacuum. It was then slurried in cyclohexane (100 ml) then filtered,washing with further cyclohexane. The crude solid was purified bydissolution in diethylether (50 ml) and passage through silica gel,washing with further diethylether. Concentration of the filtrateafforded 15.56 g (85%) of the title compound.

Mass Spectrum: Found: (M-H)⁻331; HPLC (λ=220-230 nm) RT 3.7 min.

ii) 2-(3-Chloro-4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(3-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanoneoxime (15.56 g, 46.8 mmol) in DME (64 ml) at 5° C. was added TFAA (6.6ml, 46.8 mmol) and the mixture stirred for 10 minutes. Triethylamine(19.6 ml, 140.4 mmol) was then added dropwise over 15 min. After theaddition was complete, the reaction was then warmed to room temperature.After stirring for 1 hour, iron (II) chloride (60 mg) was added and themixture was then heated to 75° C. for 1 hour then allowed to cool. Themixture was poured into water (500 ml) and extracted withdichloromethane (300 ml). The organic extracts were dried over MgSO₄ andconcentrated under reduced pressure to ca. 50 ml. This residue waspurified by filtration through a layer of silica gel washing withfurther dichloromethane. The filtrate was concentrated to dryness togive 12 g (82%) of the title compound.

¹H-NMR (DMSO-d₆): 7.32 (1H, s), 7.45 (1H, d, J=10), 7.55 (1H, t, J=9),7.90 (1H, m), 8.02 (1H, m), 8.18 (1H, d, J=7), 9.31 (1H, s).

EXAMPLE 5 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(4-Fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

This was prepared in an identical manner to Example 4i except that4-fluoroacetophenone (122.9 g, 890 mmol) was used affording 190.5 g(77%) of the title compound.

Mass Spectrum: Found: MH⁺ 299; HPLC (λ=220-230 nm) RT 5.1min (Column:Luna 3 um C18 50×2 mm ID; mobile phase A=water+0.05% trifluoroaceticacid, B=acetonitrile+0.05% trifluoroacetic acid; gradient: 100% A at t=0min, 95% B at t=8min, 100% A at t=8.01 min, 100% A at t=10 min; flowrate: 1 ml/min; temperature: 40° C.).

ii) 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (189g, 630 mmol) in DME (700 ml) at −3° C. was added methanesulfonylchloride (50.5 ml, 650 mmol) and the mixture stirred for 15 minutes.Triethylamine (182 ml, 1.31 mol) in DME (74 ml) was then added dropwiseover 15 min. After the addition was complete, the reaction was thenwarmed to 35° C. for 45 minutes. It was then cooled and filtered,washing with DME (180 ml). To the filtrate was added iron (II) chloride(0.87 g) and the mixture was then heated to 75° C. for 2.5 hour thenallowed to cool. Water (700 ml) was added, the resulting solid removedby filtration, washed with water and dried. This solid was dissolved indichloromethane (1.5 l) and purified in two portions by Biotagechromatography eluting with hexane-ethyl acetate (3:1). Combination andconcentration of the appropriate fractions gave 148.3 g (84%) of thetitle compound.

Mass Spectrum: Found: MH⁺ 281; HPLC (λ=220-230 nm) RT 6.5 min (Column:Luna 3 um C18 50×2 mm ID; mobile phase A=water+0.05% trifluoroaceticacid, B=acetonitrile+0.05% trifluoroacetic acid; gradient: 100% A at t=0min, 95% B at t=8min, 100% A at t=8.01 min, 100% A at t=10 min; flowrate: 1 ml/mn; temperature: 40° C.).

EXAMPLE 6 2-(4-Fluorophenyl)-6trifluoromethylpyrazolo[1,5-a]pyridine

To a solution of1-(4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (2.0g, 6.7 mmol) in ethyl acetate (8 ml) at 7° C. was added methanesulfonylchloride (0.52 ml, 6.7 mmol) over 3 minutes. The reaction mixture wasstirred for 5 minutes before the dropwise addition of triethylamine(1.92 ml, 13.8 mmol) over 5 minutes. The reaction temperature wasallowed to rise to 30° C. and the resulting suspension stirred at thistemperature for two hours. Iron (II) chloride (8 mg) was then added andthe mixture heated at reflux for 40 minute s before the addition offurther iron (II) chloride (5 mg) and heating at reflux for 6 hours. Thereaction mixture was then cooled to room temperature and water was added(5 ml). The phases were separated and the aqueous phase re-extractedwith ethyl acetate. The organic extracts were combined, washed withwater (5 ml) and evaporated in vacuo to give an orange-brown solid. Thesolid was triturated with isohexane (25 ml), the mixture filtered, thefilter cake washed with isohexane (2×10 ml) and dried to give the titlecompound as a dull orange solid (1.06 g, 56%).

Mass Spectrum: Found: MH⁺281; HPLC (λ=220-230 nm) RT 6.5 min (Column:Luna 3 um C18 50×2 mm ID; mobile phase (λ=water+0.05% trifluoroaceticacid, B=acetonitrile+0.05% trifluoroacetic acid; gradient: 100% A at t=0min, 95% B at t=8 min, 100% A at t=8.01 min, 100% A at t=10 min; flowrate: 1 ml/min; temperature: 40° C.).

EXAMPLE 7 2-(2-Chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i)1-(2-Chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

This was prepared in an identical manner to Example 4i except that2-chloroacetophenone (23.7 g, 153 mmol) was used affording 19.7 g (45%)of the title compound.

Mass Spectrum: Found: MH⁺−H₂0 297, 299; HPLC (λ=220-230 nm) RT 5.3 min(Column: Luna 3 um C18 50×2 mm ID; mobile phase A=water+0.05%trifluoroacetic acid, B=acetonitrile+0.05% trifluoroacetic acid;gradient: 100% A at t=0 min, 95% B at t=8 min, 100% A at t=8.01 min,100% A at t=10 min; flow rate: 1 ml/min; temperature: 40° C.).

ii) 2-(2-Chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

This was prepared in an identical manner to Example 5ii except that1-(2-chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (29.1g, 92.5 mmol) was used affording 21.2 g (77%) of the title compound.

¹H-NMR (CDCl₃): 7.14 (1H, s), 7.26 (1H, dd, J=9, J=1), 7.37 (2H, m),7.52 (1H, dd, J=7, J=2), 7.67 (1H, d, J=9), 7.90 (1H, dd, J=2, J=1),8.84 (1H, s).

EXAMPLE 82-(2-Chloro-4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(2-Chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 5.0 g, 125 mmol), DME (40 ml) and2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol).2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) wasadded in portions to the mixture under nitrogen at room temperature. Themixture was stirred at ambient temperature for one hour then at 40-45°C. overnight. Upon the completion of the reaction, the mixture wascooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) wasslowly added to the reaction mixture. The mixture was partitionedbetween diethylether (300 ml) and water (300 ml). The layers wereseparated, the organics dried over magnesium sulfate and concentrated todryness. The residue was purified by column chromatography on silicaeluting with diethylether-cyclohexane (1:3). Concentration of theappropriate fractions afforded 8.10 g (67%) of the title compound.

Mass Spectrum: Found: (M-H)⁻ 316,318; HPLC (λ=220-230 nm) RT 3.9 min.

ii)1-(2-Chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanoneOxime

A reaction vessel was charged with1-(2-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (6g, 18.9 mmol), hydroxylamine (2.63 g, 37.8 mmol), triethylamine (5.3 m37.8 mmol) and ethanol (60 ml). The reaction mixture was heated toreflux with stirring for 24 hrs. It was then cooled to room temperature,silica gel (about 25 g) was added and the mixture concentrated todryness. Purification via column chromatography on silica eluting withdiethylether-cyclohexane (3:7) and concentration of the appropriatefractions afforded an oil which solidified on standing. Trituration withcyclohexane containing a little diethylether afforded a solid which wasremoved by filtration and washed with cyclohexane to provide 2.27 g(28%) of the title compound.

Mass Spectrum: Found: MH⁺−H₂O 315,317; HPLC (λ=220-230 nm) RT 3.5 min.

iii) 2-(2-Chloro-4-fluorophenyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(2-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanoneoxime (2.65 g, 7.95 mmol) in DME (11 ml) at 5° C. was added TFAA (1.13ml, 7.95 mmol) and the mixture stirred for 10 minutes. Triethylamine(3.3 ml, 23.85 mmol) was then added dropwise over 15 min. After theaddition was complete, the reaction mixture was then warmed to roomtemperature. After stirring for 1 hour, iron (II) chloride (10 mg) wasadded and the mixture was then heated to 75° C. for 16 hours thenallowed to cool. The mixture was poured into water (100 ml) andextracted with dichloromethane (100 ml). The organic extracts were driedover MgSO₄ and concentrated to dryness. This residue was purified bycolumn chromatography on silica gel eluting withdiethylether-cyclohexane (1:4). Concentration of the appropriatefractions gave 0.3 g (12%) of the title compound.

¹H-NMR (CDCl₃): 7.07-7.14 (2H, m), 7.27 (2H, dd, J=9, J=2), 7.67 (1H, d,J=10), 7.90 (1H, dd, J=9, J=6), 8.82 (1H, s).

EXAMPLE 9 2-Phenyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-Phenyl-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 7.2 g, 180 mmol), DME (60 ml) and2-chloro-54trifluoromethylpyridine (10 g, 55.1 mmol). Acetophenone (6.83g, 56.9 mmol) in DME (20 ml) was added in portions to the mixture undernitrogen at room temperature. The mixture was stirred at ambienttemperature for one hour then at 40-45° C. overnight. Upon completion ofthe reaction, the mixture was cooled to 5° C. and 10% aqueous sodiumhydroxide solution (30 ml) was slowly added to the reaction mixturefollowed by methanol (60 ml) then hydroxylamine hydrochloride (19.1 g,357 mmol). The mixture was heated to 72° C. for 3 hours then cooled anddiluted with water (1500 ml) with stirring. The resulting solid wasremoved by filtration and dried under vacuum. The crude solid waspurified by chromatography on a 10 g silica bond-elut, eluting with anethyl acetate/cyclohexane gradient (0 to 20% ethyl acetate). The productfractions were concentrated under vacuum and triturated with ethylacetate/cyclohexane to yield 7.4 g (48%) of the title compound.

¹H-NMR (DMSO-d₆): 4.37 (2H, s), 7.32-7.38 (3H, m), 7.49 (1H, d), 7.71(2H, 8.10 (1H, dd), 8.82 (1H, s), 11.56, (1H, s).

ii) 2-Phenyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

This was prepared in an analogous manner to Example 4ii using1-phenyl-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (7.4 g, 26.4mmol) affording 3.7 g (53%) of the title compound.

¹H-NMR (DMSO-d₆): 7.26 (1H, s), 7.41-7.53 (4H, m), 7.88 (1H, d), 8.02(2H, d), 9.34 (1H, s).

EXAMPLE 10 2-(3-Methoxyphenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(3-Methoxyphenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 7.2 g, 180 mmol), DME (60 ml) and2-chloro-5-trifluoromethylpyridine (10 g, 55.1 mmol).3-Methoxyacetophenone (8.55 g, 56.9 mmol) in DME (20 ml) was added inportions to the mixture under nitrogen at room temperature. The mixturewas stirred at ambient temperature for one hour then at 40-45° C.overnight. Upon the completion of the reaction, the mixture was cooledto 5° C. and 10% aqueous sodium hydroxide solution (30 ml) was slowlyadded to the reaction mixture followed by methanol (60 ml) thenhydroxylamine hydrochloride (19.1 g, 357 mmol). The mixture was heatedto 72° C. for 4 hours then cooled and diluted with water (2000 ml) withstirring. The resulting solid was removed by filtration and dried undervacuum. The crude solid was recrystallised from methanol to yield 7.6 g(44.4%) of the title compound.

¹H-NMR (DMSO-d₆): 3.73 (3H, s), 4.36 (2H, s), 6.90 (1H, m), 7.26 (2H,d), 7.48 (1H, d), 8.10 (1H, dd), 8.83 (1H, s), 11.59 (1H, s).

ii) 2-(3-Methoxyphenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

This was prepared in an analogous manner to Example 4ii using1-(3-methoxyphenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (7.5g, 24.17 mmol) affording 2.4 g (34%) of the title compound.

¹H-NMR (DMSO-d₆): 3.83 (3H, s), 7.00 (1H, dd), 7.28 (1H, s), 7.41 (2H,m), 7.55 (1H, s), 7.57 (1H, d), 7.88 (1H, d), 9.35 (1H, s).

EXAMPLE 11 2-(3-Chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(3-Chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 14.4 g, 360 mmol), DME (120 ml) and2-chloro-5-trifluoromethylpyridine (20 g, 110 mmol) under nitrogen.3-Chloroacetophenone (15.5 ml, 200 mmol) was added in portions to themixture which was stirring at −10° C. The mixture was allowed to warm toambient temperature and then heated to 40-45° C. for 5 hours. Uponcompletion of the reaction, the mixture was cooled to 5° C. and 10%aqueous sodium hydroxide solution (60 ml) was slowly added to thereaction mixture followed by methanol (120 ml) then hydroxylaminehydrochloride (38.2 g, 550 mmol). The mixture was heated to 72° C. for 4hours then cooled and partitioned between water and ethyl acetate,washed with brine and evaporated under vacuum to dryness. The resultingsolid was slurried with cyclohexane (60 ml) and dichloromethane (10 ml)then filtered, washing with further cyclohexane. 17.5 g (53%) of thetitle compound was collected.

¹H-NMR (CDCl₃): 4.45 (2H, s), 7.3 (2H, m), 7.43 (1H, d), 7.59 (1H, d),7.76 (1H, s), 7.84 (1H, dd), 8.72 (1H, s), 8.81 (1H, s)

ii) 2-(3-Chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(3-chlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (17g, 54 mmol) in DME (170 ml) at −5° C. was added dropwise methanesulfonylchloride (4.5 m, 6.0 mmol) and the mixture stirred for 15 mins.Triethylamine (16.5 ml, 120 mmol) in DME (7 ml) was then added dropwiseover 15 min. After the addition was complete, the mixture was thenwarmed to 35° C. for 45 minutes. This was then cooled and filtered,washing with DME (20 ml). To the filtrate was added iron (II) chloride(75 mg) and the mixture heated to 70° C. for 1 hour and then allowed tocool. The reaction was concentrated to half the original volume andwater (100 ml) was added. The resulting solid was removed by filtration,washed with water and dried. The solid was dissolved in ethyl acetateand washed with water and brine and then dried over magnesium sulfate.Filtering and evaporation to dryness under vacuum afforded 14.6 g (91%)of the title compound.

Mass Spectrum: Found: MH⁺ 297/299 (3:1 ratio); HPLC (λ=220-230 nm) RT3.98 min.

EXAMPLE 12 2-(3-Benzonitrile)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(3-Benzonitrile)-2-(5-trifluoromethyl-2-pyridinyl)ethanone

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 5.46 g, 136 mmol), DME (20 ml) and2-chloro-5-trifluoromethylpyridine (7.9 g, 43.5 mmol).3-Acetylbenzonitrile (6 g, 41 mmol) in DME (60 ml) was added in portionsto the mixture under nitrogen at 0° C. The mixture was allowed to warmto ambient temperature and then heated at 40-45° C. overnight. Uponcompletion of the reaction, the mixture was cooled to 5° C. and waterwas slowly and carefully added to the reaction mixture. The mixture waspartitioned between ethyl acetate and water. The layers were separated,the organic layer washed with water and brine then dried over magnesiumsulfate and concentrated to dryness. Trituration with cyclohexane andfiltration afforded 9.8 g (82%) of the title compound.

Mass Spectrum: Found: (M-H)⁻ 289; HPLC (λ=220-230 nm) RT 3.9min.

ii) 1-(3-Benzonitrile)-2-(5-trifluoromethyl-2-pyridinyl)ethanone Oxime

A reaction vessel was charged with1-(3-benzonitrile)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (9.8 g,33.8 mmol) and dimethylformamide (100 ml). Finely ground hydroxylaminehydrochloride (7.05 g, 101 mmol) was added and the reaction heated at65° C. for 3.5 hours. After cooling to room temperature the mixture wasadded to 1 liter of water and a beige solid filtered off. Triturationwith cyclohexane, filtration and drying gave 9.6 g (93%) of the titlecompound. Mass Spectrum: Found: (M-H)⁻ 304; HPLC (λ=220-230 nm) RT2.98min.

iii) 2-(3-Benzonitrile)-6-trifluoromethylpyrazolo[1,5-a]pyridine p1-(3-Benzonitrile)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (9.55g, 31 mmol) was dissolved in DME (40 ml) and cooled to 5° C. TFAA (4.5ml, 31.7 mmol) was added and the mixture stirred for 10 minutes.Triethylamine (13.4 ml, 96.8 mmol) was then added dropwise over 15 min.After the addition was complete the reaction was warmed to roomtemperature. After stirring for 1 hour, iron (II) chloride (40 mg) wasadded and the mixture heated to 75° C. for 3 hours then allowed to cool.The mixture was evaporated to dryness, dissolved in ethyl acetate andpre-absorbed onto a pad of silica. This was purified by columnchromatography on silica gel eluting with ethyl acetate/cyclohexane(1:20). Concentration of the appropriate fractions gave 6.25 g (70%) ofthe title compound.

¹H-NMR (CDCl₃): 6.93 (1H, s), 7.28 (1H, dd), 7.6 (1H, t), 7.68 (2H, m),8.20(1H, dt), 8.26 (1H, t), 8.82 (1H, s).

EXAMPLE 132-(3,5-Dichlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

i) 1-(3,5-Dichlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanoneOxime

A reaction vessel was charged with sodium hydride (as a 60% oildispersion, 5.52 g, 138 mmol), DME (23 ml) and2-chloro-5-trifluoromethylpyridine (7.06 g, 42 mmol).3,5-Dichloroacetophenone (8.3 g, 44 mmol) in DME (23 ml) was added inportions to the mixture under nitrogen at room temperature. The mixturewas stirred at ambient temperature for one hour then at 40-45° C.overnight. Upon completion of the reaction, the mixture was cooled to 5°C. and 10% aqueous sodium hydroxide solution (23 ml) was slowly added tothe reaction mixture followed by methanol (46 ml) then hydroxylaminehydrochloride (14.5 g, 210 mmol). The mixture was heated to 72° C. for 4hours then cooled and diluted with water (1500 ml) with stirring. Theresulting solid was removed by filtration and dried under vacuum. It wasthen slurried in cyclohexane (100 ml) then filtered, washing withfurther cyclohexane. The crude solid 13.30 g (86%) was used insubsequent reactions without further purification.

Mass Spectrum: Found: (M-H)⁻ 348; HPLC (λ=220-230 nm) RT 3.83 min.

ii) 2-(3,5-Dichlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a suspension of1-(3,5-dichlorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime(13.30 g, 38 mmol) in DME (52 ml) at 5° C. was added TFAA (6.25 ml, 44mmol) and the mixture stirred for 10 minutes. Triethylamine (18.6 ml,134 mmol) was then added dropwise over 15 min. After the addition wascomplete, the reaction mixture was then warmed to room temperature.After stirring for 1 hour, iron (II) chloride (56 mg) was added and themixture was then heated to 75° C. for 1 hour then allowed to cool. Themixture was poured into water (500 ml) and extracted withdichloromethane (300 ml). The organic extracts were dried over MgSO₄ andconcentrated under reduced pressure to ca. 50 ml. This residue waspurified by filtration through a layer of silica gel washing withfurther dichloromethane. The filtrate was concentrated to dryness togive 3.2 g (25%) of the title compound.

¹H-NMR (DMSO-d₆): 7.55 (1H, s), 7.58 (1H, dd, J=9, J=2), 7.75 (1H,apparent, J=8), 8.00 (1H, d, J=10), 8.14 (2H, d, J=8), 9.38 (1H, s).

What is claimed is:
 1. A process for the preparation of a compound offormula (I)

and pharmaceutically acceptable derivatives thereof wherein: R⁰ and R¹are independently selected from H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, orC₁₋₆alkoxy substituted by one or more fluorine atoms; R² is H,C₁₋₆alkyl, C₁₋₆alkyl substituted by one or more fluorine atoms,C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H, C(O)C₁₋₆alkyl,C₁₋₆alkylsulfonyl, C₁₋₆alkoxy substituted by one or more fluorine atoms,halogen, CN, CONR⁴R⁵, CO₂H, CO₂C₁₋₆alkyl, or NHSO₂R⁴; R³ is H or phenylsubstituted by SO₂C₁₋₆alkyl or SO₂NH₂; R⁴ and R⁵ are independentlyselected from H, C₁₋₆alkyl, phenyl, phenyl substituted by one or moreatoms or groups R⁶, or together with the nitrogen atom to which they areattached form a saturated 4 to 8 membered ring R⁶ is halogen, C₁₋₆alkyl,C₁₋₆alkoxy or C₁₋₆alkoxy substituted by one or more fluorine atoms;which comprises rearrangement of an azirine of formula (II)

 wherein R⁰ to R³ are as defined for formula (I), or a protectedderivative thereof, in the presence of a transition metal catalyst and asolvent.
 2. A process as claimed in claim 1 wherein the transition metalcatalyst is a copper (II),iron (II), iron (III) or molybdenum catalyst.3. A process as claimed in claim 1 wherein the transition metal catalystis iron (II) chloride or iron (III) chloride.
 4. A process as claimed inclaim 1 wherein the solvent is an organic solvent with a boiling pointof 40° C. or greater.
 5. A process as claimed in claim 4 wherein theorganic solvent is dimethoxyethane, ethyl acetate, butyl acetate,dimethylformamide, acetonitrile or toluene.
 6. A process as claimed inclaim 1 wherein the reaction is carried out between ambient temperatureand reflux.
 7. A process according to claim 1 for the preparation of acompound of formula (I) in which R⁰ and R¹ are independently selectedfrom H, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, or C₁₋₆alkoxy substituted by oneor more fluorine atoms; R² is H, C₁₋₆alkyl, C₁₋₆alkyl substituted by oneor more fluorine atoms, C₁₋₆alkoxy, C₁₋₆hydroxyalkyl, SC₁₋₆alkyl, C(O)H,C(O)C₁₋₆alkyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxy substituted by one or morefluorine atoms; and R³ is H or phenyl substituted by SO₂C₁₋₆alkyl orSO₂NH₂.
 8. A process according to claim 1 for the preparation of acompound of formula (I) in which R⁰ and R¹ are independently H, halogen,C₁₋₆alkyl or C₁₋₆alkoxy; R² is C₁₋₃alkyl substituted by one or morefluorine atoms; R³ is H or phenyl substituted by SO₂C₁₋₃alkyl or SO₂NH₂.9. A process according to claim 1 for the preparation of a compound offormula (I) in which R³ is H.
 10. A process as claimed in claim 9 forthe preparation of a compound selected from:2-(3-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(3-chloro-4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(2-chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(2-chloro-4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-phenyl-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(3-methoxyphenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(3-chlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine;2-(3-benzonitrile)-6-trifluoromethylpyrazolo[1,5-a]pyridine; and2-(3,5-dichlorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine.
 11. Aprocess as claimed in claim 9 for the preparation of2-(3-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine.
 12. Aprocess as claimed in claim 1 for the preparation of4-[2-(3-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-benzenesulfonamide.